PROJECT I - NEUROHUMORAL AND RENAL MECHANISMS OF HYPERTENSION PROJECT SUMMARY/ABSTRACT Although impaired renal-pressure natriuresis occurs in all forms of chronic hypertension studied thus far, neurohumoral mechanisms often mediate abnormal kidney function and increased blood pressure (BP). Therefore, our research is directed toward understanding neurohumoral mechanisms that alter kidney function in hypertension caused by excess weight gain which accounts for 65-75% of human essential hypertension. We previously demonstrated that increased sympathetic nervous system (SNS) activity plays a major role in the pathophysiology of obesity-hypertension mainly by stimulation of renal sympathetic nerve activity (RSNA). We also found that leptin, an adipocyte derived hormone, contributes to SNS activation and increased BP in obesity by stimulating CNS pro-opiomelanocortin (POMC) neurons and ultimately by activation of melanocortin 4 receptors (MC4R). Our studies also indicate that the CNS POMC-MC4R pathway is a key means by which leptin regulates glucose homeostasis. Moreover, POMC activation can regulate BP and glucose independent of its effects to reduce appetite. The complex CNS circuits that mediate this differential control of cardiovascular and metabolic functions are still poorly understood. In addition, we found that the POMC-MC4R pathway may be important for BP regulation independent of leptin. The central hypothesis of this proposal is that POMC-MC4R activation in distinct areas of the hypothalamus, brainstem and spinal cord can differentially and independently regulate BP, RSNA, and metabolic functions, including appetite and energy expenditure. The proposed studies will determine which specific brain regions are most important in mediating the chronic effects of POMC-MC4R activation on RSNA, baroreflexes and BP regulation, food intake and energy expenditure, as well as the cardiometabolic responses to leptin. We will also determine the role of suppressor of cytokine signaling-3 (SOCS3) and protein tyrosine phosphatase 1B (PTP1B), in modulating leptin's actions on POMC and other neurons of the forebrain, brainstem and spinal cord in regulating cardiometabolic functions. These studies will employ unique, genetically engineered mouse models that permit us to delete or rescue MC4R, SOCS3, or PTP1B in specific neuronal populations of the hypothalamus, brainstem and spinal cord. Sophisticated physiological techniques that provide computerized chronic monitoring of cardiovascular, renal and metabolic functions, coupled with novel animal models, will permit us to unravel the specific CNS circuits by which the POMC-MC4R pathway differentially controls metabolic and cardiovascular functions, and the role of SOCS3 and PTP1B in modulating this system in obesity.